Cytomegalovirus Seropositivity and C-Reactive Protein Have Independent and Combined Predictive Value for Mortality in Patients With Angiographically Demonstrated Coronary Artery Disease

Muhlestein, Joseph B.; Horne, Benjamin D.; Carlquist, John F.; Madsen, Troy; Bair, Tami L; Pearson, Robert R.; Anderson, Jeffrey L.

doi:10.1161/01.cir.102.16.1917

Cited by 168 publications

(112 citation statements)

References 38 publications

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“…Likewise, CMV seropositivity did not predict primary coronary disease risk in large databases or prospective studies (25,26). However, CMV did predict secondary risk (death/myocardial infarction) in patients with pre-existing coronary artery disease especially in those with elevated C-reactive protein or interleukin-6 (IL-6) (27,28). Similar results were obtained in the HOPE (Heart Outcomes and Prevention Evaluation) study showing that out of the four pathogens tested (Cpn, Hpyl, hepatitis A, CMV) only CMV serostatus was predictive of cardiovascular events (29).…”

Section: Seroepidemiological Studiesmentioning

confidence: 99%

The Role of Viruses in Cardiac Allograft Vasculopathy

Valantine

2004

American Journal of Transplantation

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Considerable evidence suggests a role for viruses in transplant arteriosclerosis (TA), including observational data, experimental models and therapeutic trials implicating human cytomegalovirus (HCMV) in the progression to TA. In pediatric heart transplant patients, adenoviral genome in endomyocardial biopsies (EMB) is an important predictor of TA and graft loss. During CMV viremia, EMBs from adult patients demonstrate endothelialitis and vascular smooth muscle cell proliferation. These changes are predictors of subsequent diffuse TA. HCMV immediate early proteins (IE-1 and IE-2) increase the constitutive expression of intercellular adhesion molecule-1 (ICAM-1) independent of other intracellular cytokines. Likewise, viral chemokines such as US28 have been implicated in vascular disease because of their ability to induce smooth muscle cell migration. Recent data suggests that CMV might accelerate TA through its ability to abrogate the vascular protective effects of the endothelium-derived nitric oxide system (eNOS). Confirmation of causality requires clinical trials demonstrating that antiviral agents such as ganciclovir inhibit TA. Such studies in patients though limited to retrospective analyses, suggest that ganciclovir prophylaxis early after heart transplantation reduces the risk of TA. These observations emphasize the need for randomized controlled clinical trials to confirm a causal role for CMV (and other viruses) in TA.

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Section: Seroepidemiological Studiesmentioning

confidence: 99%

The Role of Viruses in Cardiac Allograft Vasculopathy

Valantine

2004

American Journal of Transplantation

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“…The association between CMV infection and atherosclerotic cardiovascular disease (CVD) is well-known from the literature (Blankenberg et al 2001;Gkrania-Klotsas et al 2012;Muhlestein et al 2000;Roberts et al 2010;Simanek et al 2009Simanek et al , 2011Spyridopoulos et al 2016). Since immunological processes are key features of atherosclerosis, it has been postulated that CMV infection increases cardiovascular mortality via immunological mechanisms.…”

Section: And Atherosclerotic Cardiovascular Complicationsmentioning

confidence: 99%

“…CMV seropositivity and elevated CRP, especially when in combination, are strong predictors of mortality in patients with coronary artery disease (CAD) (Muhlestein et al 2000). The association of CMV infection with death is probably partially mediated by chronic systemic inflammation.…”

Section: And Atherosclerotic Cardiovascular Complicationsmentioning

confidence: 99%

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

2017

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Cytomegalovirus (CMV) is an important pathogen for both clinical and population settings. There is a growing body of research implicating CMV in multiple health outcomes across the life course. At the same time, there is mounting evidence that individuals living in poverty are more likely to be exposed to CMV and more likely to experience many of the chronic conditions for which CMV has been implicated. Further research on the causal role of CMV for health and wellbeing is needed. However, the strong evidence implicating CMV in type 2 diabetes, autoimmunity, cancer, cardiovascular disease, vaccination, and age-related alterations in immune function warrants clinical and public health action. This imperative is even higher among individuals living in socioeconomically disadvantaged settings and those exposed to high levels of chronic psychosocial stress.

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“…CD8 T‐cell responses in CMV‐seropositive elderly are characterized by an accumulation of dysfunctional T cells with short telomeres and low proliferation potential, often considered as replicative senescent (Ouyang et al ., 2003; Griffiths et al ., 2013). Clinically, CMV has been linked to an increased incidence of coronary heart disease (CHD) in a number of studies (Ridker et al ., 1998; Muhlestein et al ., 2000; Sorlie et al ., 2000; Blankenberg et al ., 2001; Simanek et al ., 2009). It has been proposed that CMV‐driven cardiovascular mortality might be the main cause for the observed increase in mortality in CMV‐seropositive people over the age of 65 years (Savva et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

CMV seropositivity and T‐cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study

et al. 2015

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SummaryAlthough chronic infection with cytomegalovirus (CMV) is known to drive T lymphocytes toward a senescent phenotype, it remains controversial whether and how CMV can cause coronary heart disease (CHD). To explore whether CMV seropositivity or T‐cell populations associated with immunosenescence were informative for adverse cardiovascular outcome in the very old, we prospectively analyzed peripheral blood samples from 751 octogenarians (38% males) from the Newcastle 85+ study for their power to predict survival during a 65‐month follow‐up (47.3% survival rate). CMV‐seropositive participants showed a higher prevalence of CHD (37.7% vs. 26.7%, P = 0.030) compared to CMV‐seronegative participants together with lower CD4/CD8 ratio (1.7 vs. 4.1, P < 0.0001) and higher frequencies of senescence‐like CD4 memory cells (41.1% vs. 4.5%, P < 0.001) and senescence‐like CD8 memory cells (TEMRA, 28.1% vs. 6.7%, P < 0.001). CMV seropositivity was also associated with increased six‐year cardiovascular mortality (HR 1.75 [1.09–2.82], P = 0.021) or death from myocardial infarction and stroke (HR 1.89 [107–3.36], P = 0.029). Gender‐adjusted multivariate Cox regression analysis revealed that low percentages of senescence‐like CD4 T cells (HR 0.48 [0.32–0.72], P < 0.001) and near‐senescent (CD27 negative) CD8 T cells (HR 0.60 [0.41–0.88], P = 0.029) reduced the risk of cardiovascular death. For senescence‐like CD4, but not near‐senescent CD8 T cells, these associations remained robust after additional adjustment for CMV status, comorbidities, and inflammation markers. We conclude that CMV seropositivity is linked to a higher incidence of CHD in octogenarians and that senescence in both the CD4 and CD8 T‐cell compartments is a predictor of overall cardiovascular mortality as well as death from myocardial infarction and stroke.

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Cytomegalovirus Seropositivity and C-Reactive Protein Have Independent and Combined Predictive Value for Mortality in Patients With Angiographically Demonstrated Coronary Artery Disease

Abstract: CMV seropositivity and elevated CRP, especially when in combination, are strong, independent predictors of mortality in patients with CAD. This suggests an interesting hypothesis that a chronic, smoldering infection (CMV) might have the capacity to accelerate the atherothrombotic process.

Cited by 168 publications

References 38 publications

The Role of Viruses in Cardiac Allograft Vasculopathy

The Role of Viruses in Cardiac Allograft Vasculopathy

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

CMV seropositivity and T‐cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study

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